Purpose: The goal of this study is to to explore the effects of the MAO-B inhibitor, selegiline, on smoking cessation attempts. We hypothesize that subjects receiving selegiline will show higher rates of smoking abstinence as compared to subjects receiving placebo. Finally, we will determine whether acute responses to dopaminergic agents in the laboratory are predictive of smoking status in the clinical setting. Preliminary data from a small number of subjects suggests that combined pretreatment with haloperidol and amphetamine attenuates smoking satisfaction to a greater extent than either drug alone, and is a safe and tolerable treatment combination. Methods: In the original study design, regular smokers ages 18-55 participated in a two phase study. In the first phase, subjects attended four laboratory sessions, conducted on the GCRC, during which acute responses to smoking were assessed after one of four pretreatments: amphetamine (15 mg), haloperidol (2 mg), amphetamine plus haloperidol, or placebo. Subjective, behavioral and physiological responses to smoking nicotine-containing and denicotinized cigarettes were assessed at regular intervals. In a second phase, subjects participated in a clinical smoking cessation trial. All subjects received 6 weeks of treatment with selegiline (5 mg po) or placebo, beginning two weeks prior to their quit date. Drug administration is double-blind. Beginning on their quit smoking date, subjects begin receiving open-label active nicotine patch (21 mg/24 hr) in addition to the capsule. Subjects attended weekly visits during which smoking withdrawal symptoms, vital signs and smoking status were assessed. Results: Data from 9 subjects who participated in the laboratory sessions indicate that the combination of amphetamine and haloperidol attenuates positive subjective response to nicotine than either treatment alone or than placebo alone. These findings suggest that combined agonist/antagonist treatment may be more beneficial than either one alone. Results also suggest that this combined pretreatment may be more tolerable than either agonist alone or antagonist alone treatments. Data from the clinical trial have not been analyzed yet, since the study is ongoing and the code has not been broken. The requirement of participating in the laboratory session prior to quitting smoking significantly reduced our recruitment. Thus, the laboratory (GCRC) portion has been dropped. However, the clinical trial is ongoing. Significance: Nearly fifty million Americans smoke cigarettes, despite the association of smoking with substantial morbidity and mortality, including coronary heart disease, stroke, chronic obstructive pulmonary disease, peripheral vascular disease, peptic ulcers, lung cancer, and death. Unfortunately, smokers attempts to reduce their smoking are frequently unsuccessful, even with the aid of currently available pharmacological treatments. The development of more successful treatments for smoking cessation relies heavily on gaining a better understanding of the neurochemical mechanisms underlying nicotine addiction, as well as increased knowledge of non-nicotine factors that contribute to smoking behavior. This study will help to elucidate the role of dopamine in acute subjective, behavioral and physiological responses to cigarette smoking, and to assess the efficacy of a dopaminergic treatment for smoking cessation. Future Plans: The GCRC (laboratory) portion of this protocol was discontinued. The clinical trial with selegiline is ongoing. If the results are promising, a larger scale study will be conducted.